Diabetes mellitus is a group of disorders characterized by an absolute or relative deficiency of insulin produced by pancreatic ? cells. Increasing evidence now indicates that sustained endoplasmic reticulum (ER) stress plays a critical role in ? cell death in type 1 and type 2 diabetes, as well as genetic forms of diabetes including Wolfram syndrome. Targeting the ER, therefore, offers the possibility of a novel therapeutic approach to managing patients with diabetes. Despite the underlying importance of ER dysfunction and ER stress in ? cell death, there is no effective treatment for diabetes targeting the ER due to the complex etiologies of type 1 and type 2 diabetes. Our strategy for overcoming this challenge is to focus on Wolfram syndrome in which mutations in a single gene, WFS1, are involved in ER dysfunction and ? cell death. We will test the hypothesis that ER calcium stabilizers and mesencephalic astrocyte-derived neurotorophic factor (MANF) can ameliorate ER stress-mediated cell death in Wolfram syndrome, a prototype of ER stress-induced ? cell death. Our study on Wolfram syndrome may lead to novel treatments for type 1 and type 2 diabetes.